Scientists directly view immune cells interacting to avert autoimmunity

[Guest guest]

Scientists directly view immune cells interacting to avert autoimmunity

Using a new form of microscopy to penetrate living lymph nodes, UCSF

scientists have for the first time viewed immune cells at work,

helping clarify how T cells control autoimmunity.

The technique, known as two-photon laser-scanning microscopy, was

able to focus deep within the lymph node of a diabetic mouse,

allowing the researchers to show that immune cells known as T

regulatory, or Treg, cells control the destructive action of rogue

autoimmune cells when each of the two cell types interact with a

third kind of cell.

The role of the third cell type -- the antigen-presenting dendritic

cell -- in preventing autoimmune attacks of healthy tissue has been a

focus of intense research over the last 15 years. The new study

supports one contending hypothesis: It is not the interaction between

the two types of T cells, but rather the interaction of each with the

dendritic cells that leads to protection from autoimmune assaults.

Analyzing these physical interactions experimentally in living organs

or even in cell cultures has been impossible before now, the

scientists note. Their long-term aim is to use such imaging to

diagnose immune diseases such as type 1 diabetes, and to further

develop therapies that act at the level of T cell interactions.

The research, published online this week in Nature Immunology,

includes online videos of these immune cell interactions – the first

time this has been accomplished.

The scientists used fluorescent dye to mark different types of cells

so they could directly observe the interactions of the key cell types

involved in initiating autoimmune attacks and the control of their

actions by therapeutic regulatory T cells.

The " nonobese diabetic " (nob) mouse model used in the research is

considered the " prototypic " model for human type 1 diabetes, said

Qizhi Tang, PhD, UCSF adjunct assistant professor in the UCSF

Diabetes Center and lead author of the paper. The researchers expect

the findings from this study to be consistent in humans.

The UCSF team has already developed a regulatory T cell-based therapy

that can prevent and even reverse the course of autoimmune diabetes

in mouse models, and this study begins to analyze how such protection

occurs in vivo, she explained.

" By understanding the interplay between pathogenic cells and

protective cells, we hope to be able to refine the therapy to enhance

its efficacy. "

The microscopy technique is a vital new tool, Tang said. " The

function of the immune system involves multiple cell types

interacting dynamically in three dimensions, which is very difficult

to analyze in vivo -- and nearly impossible to authentically

reproduce in vitro. "

The team of immunologists and diabetes researchers used the new

microscope to show that when Treg cells are absent, the potentially

destructive autoreactive T cells, known as T helper cells, swarm

around the dendritic cells where they are primed to attack the

body’s own tissue -- the cause of type 1 diabetes, arthritis and

other autoimmune diseases.

The scientists showed that Treg cells prevent this destructive

response after they and the T helper cells independently interact

with dendritic cells. The mechanism of this protective effect remains

a major immunology puzzle. The new study suggests that regulation may

occur through direct or indirect modification of the critical antigen-

presenting dendritic cells – the scavenger cells of the immune

system that pick up and display self proteins that trigger the auto-

aggressive T cell response, said Bluestone, PhD,

distinguished professor of metabolism and endocrinology at UCSF and

senior author on the paper. Bluestone directs the UCSF Diabetes Center.

The research provides a " blueprint " of what immune regulation looks

like, says study co-author Max Krummel, PhD, UCSF assistant professor

of pathology whose lab adapted the new two-photon microscopy

technique for visualizing cell-cell interactions within the lymph node.

" We now have a pattern to look for when we try to boost or prevent

immune responses. ’Clusters’ of cells in a lymph node such as we

have seen may be indicative of certain unbridled T cell responses.

The ultimate hope here is that seeing patterns of T cell activation

may ultimately allow similar imaging to be used for diagnostic

purposes, " Krummel said.

Immunologists have long sought to harness the potent

immunosuppressive properties of the regulatory T cells to treat

autoimmune diseases and organ transplant rejection. By pinpointing

where and how regulatory T cells work in vivo in mouse models, the

researchers hope to better adapt the regulatory T cells for

therapeutic use in the future. For example, Tang said, one can

imagine that at the early stage of an autoimmune attack, it may be

very helpful to direct the therapeutic regulatory T cells to the

lymph nodes so they interact with dendritic cells before the

autoimmune T cells are able to, and thereby " stamp out the initial

sparks " before the disease spreads to the tissue.

Krummel notes that the research dispels some assumptions about

cellular movement and interaction. Many had assumed that T cells move

very little inside the lymph node. The video microscopy shows that

they move about one body length per minute, and that much of the

movement is quite directed, for example toward the dendritic cells,

rather than random activity. These directed movements are followed by

prolonged interaction between autoimmune T cells and dendritic cells

that lead to proliferation of autoimmune cells and eventually tissue

destruction.

Co-authors on the paper and collaborators in the research along with

Tang, Krummel and Bluestone are Y. , a medical student at

UCSF; Mingying Bi, MS, staff research associate; and Fife PhD,

a postdoctoral fellow, all in the UCSF Diabetes Center; Tooley,

a UCSF graduate student in pathology; and Locksley, PhD,

professor of medicine and an investigator in the

Medical Institute at UCSF.

Other co-authors are Pau Serra, a graduate student, and Pere

Santamaria, MD, PhD, professor of microbiology and infectious

diseases, both at the University of Calgary.





www.ucsf.edu

www.nature.com/ni/journal/vaop/ncurrent/abs/ni1289.html